Triazoloquinazolines, their preparation and use

ABSTRACT

Novel triazoloquinazolines of the formula I ##STR1## where A, X R 1  and R 2  have the meanings stated in the description, and their preparation are described. The compounds are suitable for controlling diseases.

The present invention relates to novel triazoloquinazolines, to aprocess for their preparation and to their use for controlling diseases.

Pyrazolo- and triazoloquinazolines having antiallergic andantiinflammatory properties have been disclosed (EP 80,176, U.S. Pat.Nos. 4,053,600, 4,128,644). Pyrazoloquinazolines which are additionallysuitable for treating thrombosis and neurological disorders have alsobeen disclosed (U.S. Pat. No. 5,153,196).

We have now found that triazoloquinaolines of the formula I ##STR2##where

A is C₁₋₅ -alkylene,

X is carboxyl which can be in the form of its salt with aphysiologically tolerated amine cation or metal cation; the radical##STR3## where R⁴ is C₁₋₈ -alkyl, cycloalkyl with 3 to 8 carbon atoms inthe ring, benzyl, one of the radicals --(CH₂)_(n) --O--R⁵ or ##STR4##where n is the number 2, 3 or 4 and

R⁵ and R⁶ are each C₁₋₃ -alkyl; hydroxyl, C₁₋₄ -hydroxyalkyl, C₁₋₄-alkylcarbonyl, nitrile O--C₁₋₄ -alkyl, tetrazolyl,carbonylaminotetrazole or unsubstituted or substituted carbamoyl, and

R¹ and R², which can be identical or different, are each hydrogen,fluorine, chlorine or bromine, trifluoromethyl, cyano, nitro, amino,C₁₋₅ -alkyl, mono- or di-C₁₋₅ -alkylamino, C₁₋₆ -alkylthio, C₁₋₆-alkylsulfenyl, C₁₋₆ -alkylsulfonyl, aminosulfonyl, di-C₁₋₆-alkylaminosulfonyl, or

R¹ and R² together are methylene- or ethylenedioxy or straight-chainC₃₋₅ -alkylene, or an aromatic or heterocyclic ring, show a differentspectrum of effects.

Preferred compounds of the formula I are those where A and X have thestated meanings, and R¹ is hydrogen or chlorine or trifluoromethyl,nitro or C₁₋₃ -alkyl, and R² is chlorine or trifluoromethyl, nitro orC₁₋₃ -alkyl, or R¹ and R² together are straight-chain C₃₋₅ -alkylene oran aromatic ring.

The following examples may be mentioned of radicals A--X in position 2of the abovementioned 1,2,4-triazolo[1,5-c]quinazolin-5-ones:

acetyl, 2-propionyl, 3-propionyl, 4-buturyl, 3-buturyl, 2-buturyl,5-valeryl, 4-valeryl, 3-valeryl and their methyl, ethyl, propyl,isopropyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl esters in each caseor their amides such as methylamides, dimethylamides, ethylamides,diethylamides, propylamides, butylamides and benzylamides;

hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl,2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, hydroxypentyl, hydroxyheptyl;

methoxymethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl,methoxybutyl, ethoxymethyl, 1-ethoxypropyl, 2-ethoxypropyl,3-ethoxypropyl, ethoxybutyl, oxomethyl, 1-oxoethyl, 2-oxoethyl,1-oxopropyl, 2-oxopropyl, 3-oxopropyl, 1-oxobutyl, 2-oxobutyl,3-oxobutyl, 4-oxobutyl, 1-oxopentyl, 2-oxopentyl, 3-oxopentyl,4-oxopentyl, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl,3-cyanopropyl, 1-cyanobutyl, 2-cyanobutyl, 3-cyanobutyl, 4-cyanobutyl.

The following may be mentioned as basic structure without thesubstituents AX:

10-Chloro-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Chloro-1,2,4-triazolo[1,5-c]quinazolin-5-one

7-Chloro-1,2,4-triazolo[1,5-c]quinazolin-5-one

8,10-Dichloro-1,2,4-triazolo[1,5-c]quinazolin-5-one

10-Bromo-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Bromo-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Bromo-1,2,4-triazolo[1,5-c]quinazolin-5-one

7-Bromo-1,2,4-triazolo[1,5-c]quinazolin-5-one

8,10-Dibromo-1,2,4-triazolo[1,5-c]quinazolin-5-one

10-Iodo-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Iodo-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Iodo-1,2,4-triazolo[1,5-c]quinazolin-5-one

7-Iodo-1,2,4-triazolo[1,5-c]quinazolin-5-one

8,10-Diiodo-1,2,4-triazolo[1,5-c]quinazolin-5-one

10-Iodo-8-chloro-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Trifluoromethyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Trifluoromethyl-8-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Trifluoromethyl-8-methanesulfonyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Methyl-8-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Ethyl-8-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Cyano-8-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-one

10-Cyano-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Cyano-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Cyano-1,2,4-triazolo[1,5-c]quinazolin-5-one

7-Cyano-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Cyano-8-methanesulfonyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Cyano-8-trifluoromethyl-1,2,4-triazolo[1,5-c]-quinazolin-5-one

10-Methyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Methyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

7-Methyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Methyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9,10-Dimethyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

7,8-Dimethyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9,10-Tetramethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

7,8-Tetramethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

9,10-Trimethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

8,9-Trimethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

7,8-Trimethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

9,10-Pentamethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

8,9-Pentamethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

7,8-Pentamethylene-1,2,4-triazolo[1,5-c]quinazolin-5-one

10-Isopropyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Isopropyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Isopropyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

7-Isopropyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9,10-Benzo-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Sulfonylamido-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Sulfonylamido-9-trifluoromethyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

10-Methylthio-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Methylthio-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Methylthio-1,2,4-triazolo[1,5-c]quinazolin-5-one

7-Methylthio-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Methylthio-8-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Trifluoromethanesulfonyl-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Trifluoromethanesulfonyl-8-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-one

10-Dimethylamino-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Dimethylamino-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Dimethylamino-1,2,4-triazolo[1,5-c]quinazolin-5-one

8,9-Methylenedioxy-1,2,4-triazolo[1,5-c]quinazolin-5-one

9,10-Methylenedioxy-1,2,4-triazolo[1,5-c]quinazolin-5-one

9-Butoxy-1,2,4-triazolo[1,5-c]quinazolin-5-one

8-Butoxy-9-cyano-1,2,4-triazolo[1,5c]quinazolin-5-one

The compounds of the formula I are prepared by intramolecularcondensation of a hydrazinoquinazoline of the formula II ##STR5## whereA, R¹ and R² have the meanings stated for formula I, R⁴ is C₁₋₈ -alkyl,cycloalkyl with 3 to 8 carbon atoms in the ring, a benzyl ring or theradical --(CH₂)--OR⁵, and Y is hydroxyl or bromine or chlorine,preferably in the presence of a dehydrating agent, in particular ofphosphorus oxychloride, polyphosphoric acid or acetic acid, with orwithout an inert solvent such as toluene, chlorobenzene, xylene orexcess acetic acid, at from 50° to 150° C., preferably at the refluxtemperature of the reaction mixture.

The esters obtained in this way can subsequently be hydrolyzed, and thefree acids can be converted into physiologically tolerated salts with anamine or a metal cation. The free acids can also be reduced to thehydroxyalkyl compounds (A--X=hydroxyalkyl) or converted by conventionalmethods into the nitriles, tetrazolemino and carbamoyl compounds.

The esters of the formula I can also be subjected to a conventionaltransesterification process appropriate for the meanings of the radicalR⁴.

The compounds of the formula I where X is carboxyl are prepared byhydrolysis of the corresponding esters, preferablyunder alkalineconditions, for example in the presence of an alkali metal hydroxide orof sodium bicarbonate, in a solvent such as water, a lower alcohol,tetrahydrofuran or mixtures thereof. The organic acids obtained in thisway are converted where appropriate into a physiologically toleratedamine or metal salt. This means, in particular, salts of the alkalimetals such as sodium and potassium, of the alkaline earth metals suchas calcium, of other metals such as aluminum, and salts of organic basessuch as morpholine, piperidine, mono-, di- and triethanolamine ortris(hydroxymethyl)aminomethane, which are generally known to theskilled worker.

Carboxylic acids of the formula I can furthermore be prepared byhydrogenolysis of the corresponding benzyl esters by conventionalmethods as described, for example, in Houben-Weyl, Vol. IV/1c, pages 381et seq. The reaction takes place in the presence of a catalyst such asplatinum, palladium or nickel, expediently on a support, in particularcarbon, in a solvent such as a lower alcohol, especially methanol,acetic acid or a dialkylformamide, in particular dimethylformamide, atfrom 0° C. to the boiling point of the solvent, and preferably underonly slightly elevated pressure.

Amides of the formula I where X is carbamoyl, are obtained by reactingthe esters with ammonia or amines in the presence of a solvent such aswater, a lower alcohol, an aqueous alcoholic solution ordialkylformamide at from 0° C. to the reflux temperature of the system.

Treatment of primary amides with a dehydrating agent such as phosphoruspentoxide, phosphorus oxychloride or thionyl chloride results in thenitriles of the compounds of the formula I where X is a nitrile group.The reaction is generally carried out with an excess of dehydratingagent at the reflux temperature of the mixture. It is possible whereappropriate to carry out the reaction in the presence of an inertsolvent such as benzene or ethylene chloride.

The compounds of the formula I where X is a tetrazole radical aresynthesized by conventional methods as described, for example, in Synth.1973, 80, by reacting the amides with hydrazoic acid or one of itssalts, for example with alkali metal or alkaline earth metal azides, inthe presence or absence of Lewis acids such as aluminum chloride and tinchloride or of ammonium chloride. The combination of sodium azide withchloride is preferred. The reaction is generally carried out in thepresence of an inert solvent such as benzene, tetrahydrofuran ordimethylformamide at from room temperature to 150° C. The tetrazolylcompounds are highly acidic and can be converted in a conventional wayinto a salt with a physiologically tolerated amine cation or metalcation.

Reduction of carboxylic acids, in particular of an ester of a compoundof the formula I, by conventional processes, for example using a complexmetal hydride such as lithium borohydride, in the presence of an ethersuch as tetrahydrofuran as solvent provides the hydroxymethyl compoundsof the formula I (X=CH₂ OH). The reduction is preferably carried out atthe boiling point of the reaction mixture.

Compounds of the formula I with a carbonylaminotetrazole radical for X(X=CO--NH--CHN₄) can be obtained by conventional methods by condensationof the basic carboxylic acid with 5-aminotetrazole of the formula III##STR6## The reaction is usually carried out in an inert solvent suchas, for example, methylene chloride, dioxane, tetrahydrofuran ordimethylformamide, preferably in the presence of a condensing reagentknown from peptide chemistry, such as N,N'-carbonyldiimidazole orN,N'-dicyclohexylcarhodiimide, at from 20° C. to 120° C.

Compounds of the formula I where X is an unsubstituted or substitutedcarbamoyl radical can also be prepared in a similar way from thecorresponding acids.

If the substituents R¹ and R² are not yet present in the startingcompounds, they can also be introduced subsequently. This can take placeby an electrophilic aromatic substitution of a resulting compound of theformula I where R¹ and/or R² are hydrogen by conventional methods asdescribed, for example, in Houben-Weyl, Vol. X/1, pages 471 et seq.,Vol. IX, pages 572 et seq. and Vol. V/3, page 873. Thus, the nitrationcan be carried out with a mixture of sulfuric and nitric acids at roomtemperature, the sulfonation can be carried out, for example, withchlorosulfonic acid at from room temperature to 150° C., and thechlorination can be carried out with sulfuryl chloride at from 20° C. to100° C.

The starting compounds of the formula II are prepared in a conventionalway by condensing a hydrazinoquinazoline of the formula IV ##STR7##where R¹, R² and Y have the abovementioned meanings, with a dicarboxylicester halide or a dicarboxylic diester. When an ester halide, preferablya chloride, is used, the reaction expediently takes place at from -30°C. to 70° C., preferably at room temperature, in an inert solvent suchas dimethylformamide, dioxane, tetrahydrofuran or methylene chloride.The reaction is preferably carried out in the presence of tertiaryorganic bases such as triethylamine or pyridine.

The reaction of IV with esters can be carried out with or withoutsolvents such as toluene, chlorobenzene or diphenyl ether, at from about20° C. to the reflux temperature of the mixture.

Another process for preparing starting compounds of the formula IIcomprises reacting an acylhydrazine of the formula V ##STR8## where R⁴has the abovementioned meaning, with a quinazoline of the formula VI##STR9## where R¹, R² and Y have the abovementioned meanings, and X is anucleofugic leaving group, preferably a halogen atom, such as chlorine.The reaction is carried out at from 0° C. to 50° C. in an inert solventsuch as ethanol, methylene chloride, toluene, tetrahydrofuran ordimethylformamide, preferably with an excess of V.

Synthesis of compounds of the formulae IV and VI is described in EP 80176.

The compounds I according to the invention are suitable aspharmaceutical agents for human and veterinary medicine and can be usedto produce drugs for the treatment of neurodegenerative disorders andneurotoxic disturbances of the central nervous system and for producingspasmolytics, antiepileptics, anxiolytics and antidepressants.

The pharmacological activity of the compounds I according to theinvention was investigated on isolated membrane material from ratcerebra. To do this, the membrane material was treated in the presenceof the compounds according to the invention with the radiolabeledsubstances ³ H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (³H-AMPA) and ³ H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (³H-AMPA) and ³ H-5,7-dichlorokynurenic acid, the latter binding tospecific receptors (AMPA receptor and NMDA receptor(N-methyl-D-aspartate) respectively). The radioactivity of the treatedmembranes was subsequently measured by scintillation counting. Theamounts of bound ³ H-AMPA and ³ H-5,7-dichlorokynurenic acid, or in eachcase the amounts of these radiolabeled substances displaced, weredetermined from the bound radioactivity. The dissociation constant K_(I)(I=inhibitor) resulting from this, which is a measure of the displacingeffect of the agent according to the invention, was found by iterativenonlinear regression analysis using the Statistical Analysis System(SAS) on an IBM computer, similar to the Ligand program of P. J. Munsonor D. Rodbard (Analytical Biochem. 107, 220 (1980), Ligand: VersatileComputerized Approach for Characterization of Ligand Binding Systems).

The following in vitro investigations were carried out:

1. Binding of ³ H-2-amino-3-hydroxy-5-methyl-4-isoxanolpropionic acid (³H-AMPA)

To prepare the membranes, freshly removed rat cerebra were homogenizedtogether with about 15 times the volume of a buffer solution A composedof 30 mM α,α,α-tris(hydroxymethyl)methylamine hydrochloride (TRIS-HCl)and 0.5 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4, using anUltra-TURRAX. The suspension was centrifuged at 48,000 g for 20 min.After removal of the supernatant liquid, the proteinaceous membranematerial present in the sediment was washed three times by suspension inbuffer solution A and subsequent centrifugation at 48,000 g for 20minutes each time. The membrane material was then suspended in 15 timesthe volume of buffer solution A and incubated at 37° C. for 30 minutes.The protein material was subsequently washed twice by centrifugation andsuspension and stored at -70° C. until used.

For the binding assay, the protein material was thawed at 37° C. andwashed twice by centrifugation at 48,000 g (20 minutes) followed bysuspension in a buffer solution B composed of 50 mM TRIS-HCl, 0.1 Mpotassium thiocyanate and 2.5 mM calcium chloride, pH 7.1. Subsequently0.25 mg of membrane material, 0.1 μCi of ³ H-AMPA (60 Ci/mmol) andcompound I were dissolved in 1 ml of buffer solution B and incubated onice for 60 minutes. The incubated solution was filtered through a CF/Bfilter (from Whathman) which had previously been treated with a 0.5%strength aqueous solution of polyethyleneimine for at least 2 hours. Thefiltrate [sic] was then washed with 5 ml of cold buffer solution B inorder to separate bound and free ³ H-AMPA from one another. After theradioactivity of the bound ³ H-AMPA in the membrane material had beenmeasured by scintillation counting, the K_(I) was determined bysubjecting the displacement plots to regression analysis.

The following results were obtained:

    ______________________________________                                        Example No.  AMPA binding Ki [μM]                                          ______________________________________                                        13           3.4                                                              14           0.6                                                              15           1.0                                                              18           0.6                                                              19           0.7                                                              20           0.6                                                              ______________________________________                                    

2. Binding of ³ H-5,7-dichlorokynurenic acid

To prepare the membrane material, freshly removed rat cerebra werehomogenized together with about 10 times the volume of a buffer solutionA' composed of 50 mM TRIS-HCl and 10 mM EDTA, pH 7.4. The suspension wascentrifuged at 48,000 g for 20 minutes. After removal of the supernatantliquid, the membrane material present in the sediment was washed twiceby suspension in buffer solution A' and subsequent centrifugation for 20minutes each time and suspension. After resuspension of the membranes inbuffer solution A' and freezing in liquid nitrogen, the suspension wasthawed again at 37° C. and, after another wash step, incubated at 37° C.for 15 minutes. The protein material was subsequently washed bycentrifugation and suspension four times and was stored at -70° C. untilused.

For the binding assay, the protein material was thawed at 37° C. andwashed twice by centrifugation at 48,000 g (20 minutes) followed bysuspension in a buffer solution B' composed of 50 mM TRIS-HCl, pH 7.4.Subsequently 0.15 mg of membrane material, 0.3 μCi of ³H-5,7-dichlorokynurenic acid (16 Ci/mmol) and compound I were dissolvedin 1 ml of buffer solution B' and incubated on ice for 30 minutes. Theincubated solution was centrifuged at 150,000 g for 2 minutes. Afterremoval of the supernatant liquid, the sediments were suspended twice in1.5 ml of cold buffer solution B' each time. After the radioactivity ofthe ³ H-5,7-dichlorokynurenic acid bound to the membranes in thesediment had been measured, the K_(I) was found by subjecting thedisplacement plots to regression analysis.

The following results were obtained:

    ______________________________________                                                     Binding of dichloro-                                             Example No.  kynurenic acid Ki [μM]                                        ______________________________________                                        4            1.75                                                             13           0.5                                                              14           0.17                                                             15           0.4                                                              16           0.1                                                              18           0.65                                                             19           0.3                                                              20           0.4                                                              21           0.8                                                              ______________________________________                                    

The drug preparations are produced in a conventional way, eg. by mixingthe agent with the other conventional excipients and diluents.

The drug preparations can be administered in various ways such asorally, parenterally, subcutaneously, intraperitonally [sic] andtopically. Thus, possible formulations are as tablets, emulsions,solutions for infusion and injection, pastes, ointments, gels, creams,lotions, dusting powders and sprays.

The drug preparations according to the invention contain atherapeutically effective amount of the compound I in addition toconventional pharmaceutical ancillary substances. The agents can bepresent in the conventional concentrations for local external use, eg.in dusting powders and ointments. As a rule, the agents are present inan amount of from 0.001 to 5% by weight, preferably 0.02 to 0.5% byweight.

On internal use, the preparations are administered in single doses. From0.1 to 50 mg, preferably 0.1 to 10 mg, of agent are given per kg of bodyweight in a single dose. The preparations can be administered in one ormore dosages each day depending on the nature and severity of thedisorders. The daily dose is usually from 0.1 to 100 mg per kg of bodyweight on oral administration and from 0.01 to 10 mg per kg of bodyweight on parenteral administration.

The pharmaceutical preparations according to the invention contain,besides the agent, the conventional excipients and diluents appropriatefor the desired mode of administration. For local externaladministration it is possible to use pharmaceutical ancillary substancessuch as ethanol, isopropanol, ethoxylated castor oil, ethoxylatedhydrogenated castor oil, polyacrylic acid, polyethylene glycol,polyethylene glycol stearate, ethoxylated fatty alcohols, liquidparaffin, petrolatum and wool fat. Suitable examples for internaladministration are lactose, propylene glycol, ethanol, starch, talc andpolyvinylpyrrolidone.

It is furthermore possible for antioxidants such as tocopherol andbutylated hydroxyanisole, as well as butylated hydroxytoluene,flavor-improving additives, stabilizers, emulsifiers and bleaches to bepresent.

The substances present in the preparation in addition to the agent, aswell as the substances used in the production of the pharmaceuticalpreparation must be toxicologically acceptable and compatible with theagent in each case.

The following examples illustrate the invention in detail.

A. PREPARATION OF STARTING COMPOUNDS EXAMPLE a

2-Chloro-4-N(N'-ethylsuccinylhydrazino)quinazoline

3 g of 2-chloro-4-hydrazinoquinazoline were suspended in 100 ml ofmethylene chloride and 2 ml of triethylamine and, at 0° C., 3 g of ethylsuccinyl chloride were added dropwise. The mixture was stirred at roomtemperature overnight, and the precipitate was filtered with suction,washed with water and dried. Yield: 4.1 g (82%).

The following were prepared similarly from the appropriatehydrazinoquinazolines and ester chlorides:

2-Chloro-4-N(N'-ethylglutarylhydrazino)quinazoline

2-Chloro-4-N(N'-ethylmalonylhydrazino)-9-nitroquinazoline

2-Chloro-8,9-dimethyl-4-N(N'-ethylsuccinylhydrazino)quinazoline

B. PREPARATION OF THE FINAL PRODUCTS EXAMPLE 1

Ethyl 3-(1,2,4-triazolo[1,5-c]quinazolin-5-on-2)propionate

32 g of 2-chloro-4-N(N'-ethylsuccinylhydrazino)quinazoline were refluxedin 500 ml of acetic acid for 2 h. The solvent was removed bydistillation, and the residue was treated with methanol, filtered offwith suction and dried. Yield: 19.4 g (68%); m.p. 208°-210° C.

The following compounds were prepared in a similar way starting from theappropriate compounds:

2. Methyl 4-(1,2,4-triazolo[1,5-c]quinazolin-5-on-2)-butyrate, m.p.176°-179° C.

3. Ethyl 2-(1,2,4-triazolo[1,5-c]quinazolin-5-on-2)-acetate, m.p.206°-210° C.

4. Methyl3-(8,9-dimethyl-1,2,4-triazolo[1,5-c]quinazolin-5-on-2)propionate, m.p.253°-258° C.

5. Ethyl3-(8-trifluoromethyl-1,2,4-triazolo[1,5-c]-quinazolin-5-on-2)propionate,m.p. 220°-222° C.

EXAMPLE 6

4-(1,2,4-Triazolo[1,5-c]quinazolin-5-on-2)butyric acid

3.5 g of substance from Example 2 were stirred in 70 ml of 1 N sodiumhydroxide solution at room temperature overnight. The solution wasextracted with CH₂ Cl₂, the aqueous phase was adjusted to pH 1 with 1 Nhydrochloric acid, and the precipitate was filtered off with suction,washed with water and dried. Yield: 2.8 g (84%); m.p. 266°-270° C.

The following compounds were prepared in a similar way:

    ______________________________________                                         ##STR10##                                                                    Ex.      R.sup.1    R.sup.2   n   M.p. [C.]                                   ______________________________________                                         7       H          H         2   315-317                                      8       9-NO.sub.2 H         2   250-254                                      9       9-NO.sub.2 H         3   153-157                                     10       H          H         1   330-335                                     11       9-NO.sub.2 H         1   315-320                                     12       9-Cl       H         2   300-301                                     13       8-NO.sub.2 H         3   234-236                                     14       8-NO.sub.2 H         2   272-273                                     15       8-NO.sub.2 9-NO.sub.2                                                                              2   224-226                                     16       8-CH.sub.3 9-CH.sub.3                                                                              2   >350                                        17       8-CF.sub.3 9-NO.sub.2                                                                              2   241-243                                     18       8-CF.sub.3 H         2   293-295                                     19       7,8-benzo            2   313-319                                     20       8,9-benzo            2   337-339                                     ______________________________________                                    

EXAMPLE 21

3-(8,9-Dimethyl-1,2,4-triazolo[1,5-c]quinazolin-5-on-2)propionic acidbenzylamide

1.7 g of acid from Example 16 were stirred with 1.2 g of1-hydroxybenzotriazole hydrate and 1.4 g of dicyclohexylcarbodiimide in15 ml of DMF for 90 min, and subsequently a solution of 0.65 g ofbenzylamine in 5 ml of DMF was added, and the mixture was stirred atroom temperature for a further 15 h. The mixture was filtered, thefiltrate was evaporated under reduced pressure, and the residue waswashed with methylene chloride. Yield: 0.65 g (33%); m.p. 289°-294° C.

EXAMPLE 22

Ethyl 2-(9-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-on-2) acetate

1 g of ester (Example 3) was stirred in a mixture of 10 g ofconcentrated sulfuric acid and 0.21 ml of concentrated nitric acid for 4h. The mixture was poured into ice, and the precipitate was filtered offwith suction, washed with water and dried. Yield: 0.75 g; m.p. 188°-190°C.

The following were prepared in a similar way,

23. Ethyl 3-(9-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-on-2)propionate,m.p. 120°-126° C.

24. Methyl 4-(9-nitro-1,2,4-triazolo[1,5-c]quinazolin-5-on-2)butyrate,m.p. 192°-196° C.

EXAMPLE 25

Ethyl3-(8-trifluoromethyl-9-nitro-1,2,4-triazolo{1,5-c]-quinazolin-5-on-2)propionate

5 g of ester (Example 5) were added in portions at 0° C. to a mixture of10 ml of fuming nitric acid and 14.5 ml of concentrated sulfuric acid.After 2 h, the reaction mixture was poured into ice and extracted withethyl acetate, the organic phase was dried and concentrated, and theresidue was chromatographed on silica gel with methylenechloride/methanol (50:1). Yield: 2.0 g; m.p. 166°-168° C.

The following was prepared in a similar way:

EXAMPLE 26

Ethyl 3-(8,9-dinitro-1,2,4-triazolo[1,5-c]quinazolin-5-on-2)propionate,m.p. 170°-172° C.

We claim:
 1. A triazoloquinazoline of the formula I ##STR11## where A isC₁ -C₅ -alkylene,X is carboxyl which can be in the form of its salt witha physiologically tolerated amine cation or metal cation; the radical##STR12## where R⁴ is C₁ -C₈ -alkyl, and R¹ and R², which can beidentical or different, are each hydrogen, fluorine, chlorine orbromine, trifluromethyl, nitro, C₁₋₅ -alkyl, or R¹ and R² together are abenzo group.
 2. A pharmaceutical composition for treating neurotoxicdisturbances of the central nervous system comprising an effectiveamount of a compound of the formula I as defined in claim 1 and apharmaceutically acceptable carrier therefor.
 3. A method for treatingneurotoxic disturbances of the central nervous system in mammals, whichcomprises administering to the mammalian host a pharmaceuticallyeffective amount of a compound of the formula I as defined in claim 1.